Despite long-term investment, influenza continues to be a significant worldwide problem. Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S. and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza cases are also very significant resulting in up to 49,000 deaths in the U.S. annually. Human volunteer influenza virus challenge studies are continuing at the NIH Clinical Center using both a 2009 influenza A/H1N1 virus and a 2012 influenza A/H3N2 virus under FDA-approved INDs. A healthy volunteer screening study continued at the Clinical Center to identify patients who will qualify and be available for current and future challenge studies. In addition, a long-term study consisting of a 2 year follow up of patients who participated in previous challenge studies also continued to enroll with the first patients completing their 2 years follow up. These clinical studies over the past year have also included Phase II challenge studies to evaluate novel therapeutic and vaccines. One study under a CRADA with Crucell/Johnson and Johnson is evaluating a novel monoclonal therapeutic antibody, while another Phase II study under a CRADA with SEEK completed enrollment this year to evaluate a novel universal influenza vaccine. We also continue to further develop the challenge model through the development of other seasonal influenza A and B challenge viruses and continued collaboration with DCR on the development of FLUPRO, a validated questionnaire for measuring the severity of influenza infections. This past year has lead to significant breakthroughs in terms of understanding influenza immunity and issues to consider in development of universal vaccine. The challenge studies have demonstrated the importance of anti-neuraminidase antibodies over anti-HA and anti-HA stalk antibodies, the benefit of T-cell immunity, and the potential of mucosal immunity. This has lead to the co-development of multiple vaccine candidates between the LID CSU and LID VPES. It has also lead to the initiation of new challenge studies to further evaluate these forms of immunity. In addition to these clinical studies we continued our collaborations with Rockefeller University, Stanford, FDA, and within NIAID to further study human influenza infection and how it relates to other viral infections. In addition, we have performed further analysis of data collected from the previously completed challenge studies. We recently started the first human challenge study to assess the mucosal immune response after vaccination and challenge.